Use of erythropoientin and iron preparations for producing pharmaceutical combination preparations for treating rheumatic diseases

ABSTRACT

The present invention is concerned with the use of individual administration forms of an erythropoietin preparation and a physiologically compatible iron preparation corresponding to an equivalent amount of 1-40 mg of iron ions for the production of a pharmaceutical combination preparation for the treatment of rheumatic diseases.

BACKGROUND OF THE INVENTION

The present invention is concerned with the use of erythropoietin andiron preparations for the production of pharmaceutical combinationpreparations. These combination preparations comprise individualadministration forms of an erythropoietin preparation and aphysiologically compatible iron preparation corresponding to anequivalent amount of 1-40 mg of iron ions for the treatment of rheumaticdiseases.

Pharmaceutical combination preparations containing erythropoietin andiron preparations are known from PCT Patent Application WO 97/09996. Thepreparations are utilized especially for the optimization oferythropoiesis in the treatment of illnesses in which a stimulation oferythrocyte formation is striven for.

The use of erythropoietin for the treatment of chronic inflammations,especially of rheumatoid arthritis, is known from WO 96114081.

The therapeutic treatment of patients suffering from rheumatic diseaseshas hitherto still not been possible using a satisfactory treatmentregimen. In this respect, there exists a need for improved treatmentmethods, such as, for example, in the treatment of rheumatoid arthritis,lupus erythematosus, Bechterew's disease, etc.

Rheumatic diseases of the locomotor system and inflammatory jointdiseases are worldwide one of the main causes of chronic pains andsevere bodily damage. All elements of the musculoskeletal system are ina dynamic equilibrium and their form, structure and functional statechange constantly depending on loading and mechanical requirements. Thissystem is susceptible to trauma and responsive to localized and systemicinflammatory disorders. Acute inflammatory conditions or tissue injuriesoften result in chronic conditions, possibly because of the constantmovements and mechanical loadings.

Joint diseases belong to diseases of the locomotor system and aresub-divided into those which concern the periarticular tissue and thosewhich are true joint diseases (e.g. arthrosis). Symptoms and diagnosescan often lead back to a systemic, generalized disease or also toillnesses which primarily emanate from another system or organ.

Immune-mediated inflammation plays an important role in the pathologicalcourse of rheumatic disorders. In many cases immune-mediatedinflammation is the basis of numerous systemic connective tissuediseases. Infectious processes are also of significance, primarily indiseases such as rheumatic fever, Lyme borreliosis or reactivearthritis. The etiology of rheumatic diseases may be multi-factorial,with genetic reasons and environmental effects also having an importantinfluence.

Pain is a major symptom of most rheumatic diseases, especially of jointdiseases. Hitherto, the causes of joint pain have been largely unclear.A therapeutic control of joint pain is possible at present only in aninadequate manner. Also, the decisive factors of a loss of function havepreviously not been completely clear. Many of the most important jointdiseases show in their incidence remarkable differences between sexes;thus, SLE occurs primarily in women, while ankylosing spondylitis occursmore frequently and in more severe form in men. The reasons for this arelikewise unclear.

The incidence, prominence and consequences of diseases of the locomotorsystem depend on age and sex. Some diseases occur only in childhood(juvenile chronic arthritis); others, such as SLE or ankylosingspondylitis, begin mainly in young adults, polymyalgia rheumatica andgranulomatous arteritis on the other hand almost never occur before theage of 55. cP, SLE, gout and other serious inflammatory rheumaticdiseases show a different initial prominence with increased age. Most ofthese diseases of the locomotor system cause chronic pain.

No medicament having a satisfactory activity is available for healingthese chronic rheumatic diseases. The therapeutic principles used in thetreatment are frequently based on and often depend on factors such asthe age and overall situation of the patient and the extent ofinflammatory activity and of the consequences (pain intensity, extent ofimpediment). The treatment plan used in practice for patients withsevere diseases of the locomotor system is composed of differentmeasures and is in this respect often dependent on the treatingphysician. A uniform and generally accepted treatment method hashitherto not been established.

SUMMARY OF THE INVENTION

It has surprisingly now been found that a positive influence on theoverall disease picture in patients with rheumatic diseases and animprovement in the general health and the quality of life of thesepatients can be achieved with the aid of an optimal amount of EPO andiron in the form of a corresponding combination preparation. Further, anoptimal activity of EPO and respectively, of the iron preparationemployed is achieved. In particular, the costs of the treatment with EPOcan be clearly reduced in that, for example, lower dosages of the activesubstance can be administered. The combination preparations inaccordance with the invention are especially suitable for the treatmentof inflammatory joint diseases. Further, in many patients a clearalleviation of pain can be achieved.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Effects of treatment with EPO and iron sucrose according toExample 1. Isometric Muscle Strength (MSI) fatigue scale (MAF) andvitality scores are shown.

FIG. 2: Effects of treatment with EPO and iron sucrose according toExample 1. Disease Activity Score (DAS) Rheumatoid Arthritis DiseaseActivity Index (RADAI) and Acute Phase Parameter C-reactive protein(CRP) are shown.

DETAILED DESCRIPTION OF THE INVENTION

In the meaning of the present invention there are used especially thosepharmaceutical combination preparations which contain 250-20,000 U of anerythropoietin preparation and 1-40 mg of an equivalent amount of ironions of physiologically compatible iron preparation, whereby theerythropoietin preparation and the iron preparation can be present inseparate administration form or in a single administration form. Thecombination preparations preferably contain 1-30 mg, particularly 3-20mg, of an equivalent amount of iron ions of a physiologically compatibleiron preparation, especially a Fe(II) or Fe(III) complex.

As suitable erythropoietin preparations in the meaning of the presentinvention there come into consideration those active substances whichare comparable with respect to the physiological effect of human EPOs.Suitable EPO preparations are, for example, recombinant human EPO(rhEPO; see European Patent EP 0,205,564 or EP 0,411,678) or alsocorresponding modifications of these proteins. As modifications therecome into consideration, for example, such proteins with molecularweights higher or lower than 34,000 Da (molecular weight of urinaryEPO), likewise isoforms of the enzyme or proteins with differentglycosylation. In particular, proteins chemically modified by PEG(polyethylene glycol) can also be used. Further, there basically alsocome into consideration such proteins which are derived by deletions,substitutions or additions of one or more amino acids of the amino acidsequence of the natural EPO with a length of 166 amino acids. Theseproteins have essentially comparable physiological properties to rhEPO.In particular, these proteins have biological properties which causebone marrow cells to increase the production of reticulocytes and redblood corpuscles and/or to increase haemoglobin synthesis or ironuptake. In place of these proteins there can also be used low molecularsubstances, which are denoted as EPO mimetics, and which bind to thesame biological receptor. These mimetics can preferably also beadministered orally. The amount of such proteins or mimetics to beadministered is determined by comparing the biological activity betweenEPO and these active substances.

Oral iron resorption is only about 1 mg per day and under extremeloading (in the case of oral administration of about 300 mg Fe(III)/day)less than 3 mg per day. Therefore, the intravenous administration ofiron preparations is increasingly preferred. Two intravenouslyadministerable iron preparations are available on the German medicamentmarket at present. These are the medicaments “Ferrlecit” and “FerrumVites”. “Ferrlecit” is an iron(III) gluconate complex, while “FerrumVites” is an iron(III) hydroxide saccharate complex.

The manifold problems of a high dosage, long-term oral iron therapy canbe circumvented relatively simply by the intravenous, subcutaneousadministration of physiologically compatible iron(III) salts duringhaemodialysis treatment, since in this case a safe intravenous,subcutaneous access exists and the injection can be effected withoutfurther burden on the patients. The intravenous administration of ironpreparations is, however, not trivial, since with the administration ofhigh doses side effects have to be taken into consideration, primarilywhen large amounts have to be injected relatively rapidly. Further, theintravenous administration of iron preparations causes problems up toacute phase reactions when the iron dose given is too high or is notoptimally correlated with the EPO dose. Iron poisoning can also occur inthe case of a too high dosage of iron-containing preparations.Elementary iron has a toxic effect on the gastrointestinal tract and onthe cardiovascular and central nervous systems. The oral lethal dosageof elementary iron varies between 200 and 250 mg/kg. The most frequentlyused iron tablets are ferrous sulphate (contains about 20% elementaryiron), ferrous fumarate (contains about 30% elementary iron) and ferrousgluconate (contains about 10% elementary iron).

Iron preparations in the meaning of the present invention are oral orparenteral administration forms. These can be basically individualpreparations, which contain a physiologically compatible iron salt or aniron complex compound as the active substance, or also combinationpreparations, which in addition to the physiologically compatible ironpreparation contain other active substances, such as e.g. vitamins,folic acid, thiamine chloride, riboflavin, pyridoxine, ascorbic acid,nicotinamide, calcium pantothenate, etc.

Physiologically compatible iron salts or iron complex compounds are, forexample, iron(II) sulphate, iron(II) fumarate, iron(II) citrate,iron(II) gluconate, iron(II) succinate, iron(II) chloride, iron(II)glycine sulphate complex, iron(II) aspartate, sodium iron(III) gluconatecomplex, iron(III) hydroxide polymaltose complex or ferrisorbitolcitrate complex. Preferred iron preparations are especially Fe(III)complexes, especially those with a molecular weight between 30,000 and100,000 D. Fe(III) saccharate is especially preferred. Here, referencecan be made to the commercially available preparation “Ferrum Vitis”(manufactured by Neopharma, Germany). By virtue of the low iron dosagein accordance with the invention it is also possible to utilize labileiron complexes, such as iron gluconate (mol. wt. about 1,000 D;Ferrlecit), in the combination preparation, although these labile ironcomplexes liberate relatively large amounts of ionized iron, which wouldlead to toxicities in the case of the intravenous administration oflarge amounts.

Hereinafter there is to be understood with respect to the amount of theiron preparation basically the equivalent amount of iron ions, Fe(II) orFe(III) ions, to be administered. By this standardization the amount ofan arbitrary iron preparation can be calculated on the basis of itsknown molecular weight. In the case of iron(III) gluconate×2 H₂O, forexample, the amount of iron is 80.5 mg when an amount of 695 mg of theiron preparation is administered. When, for example, 280 mg of anhydrousiron(II) succinate are administered, the amount of iron is 95.2 mg.

In the meaning of the present invention there should be understood underthe term “combination preparation” not only those medicament packs inwhich the EPO preparation and the iron preparation are presented injuxtaposition in a finished marketable unit pack (so-called combinationpack), but also those medicament packs which either contain a suitableamount of an EPO preparation or a suitable amount of an iron preparationin the form of the respective individual preparations, with theindividual preparations with respect to the amount of contents beingpresented such that they can be administered in the meaning of theinvention for the combined dose with the respective other preparation.In these cases there is usually enclosed with the preparations from thepharmaceutical manufacturer or the medicament importer a medicamentpackage insert which is required by law in many countries and in whichare contained directions or information concerning the combined dose ofthe individual preparations. Preferably, the combination preparationscan be present in a single administration form in which the respectiveamounts of the EPO preparation and the iron preparation are present injuxtaposition in one container.

For the treatment of haemodialysis patients, the combination preparationin accordance with the invention contains, for example, 250 to 15,000 U(the abbreviation “IU” for International Units can also be used in placeof the abbreviation “U”) of an EPO preparation, especially 500 to 10,000U. Preferred dosages are 250 U, 500 U, 1,000 U, 2,000 U, 5,000 U, 7,500U and 10,000 U per individual dose. The amount of iron ions isadvantageously up to 30 mg, preferably 3-20 mg, especially 5-20 mg, andparticularly about 10 mg. For the treatment of anaemia patients, theoptimal dosage is 500 to 10,000 U, preferably about 1,000-3,000 U. Inthis case, the amount of iron ions is advantageously up to 30 mg, forexample 3-15 mg and especially about 5 mg.

The concentrations in accordance with the invention of EPO and of theiron complex permit in their combination an optimal adjustment andtreatment of patients suffering from rheumatic diseases and in the caseof intravenous iron therapy do not lead to acute phase reactions.

The treatment with the combination preparation is effected once to fivetimes weekly, preferably up to four times weekly, with the total amountof iron per patient not exceeding 100 mg per week. In the treatment ofpatients with rheumatic diseases, a total amount of 80 mg, especially 50mg, of iron ions per week should advantageously not be exceeded. Aparticular advantage of the combination preparation in accordance withthe invention in clinical practice lies in the fact that it can be usednot only in the correction phase, but also in the maintenance phase ofthe iron therapy of haemodialysis patients without causing toxicities.Hitherto, different amounts of iron have been administered, withinitially higher dosages of iron ions being administered in thecorrection phase compared with the maintenance phase. Surprisingly, thisdifferent dosing is no longer required when using the combinationpreparations in accordance with the invention. The amount of theerythropoietin preparation and of the iron preparation are correlatedoptimally to each other in the combination preparation in accordancewith the invention such that a differentiation between maintenance doseand correction dose is not required. Hereby, an increased safety in thetreatment of patients is achieved, since the possibility of mistakeswith respect to the optimal dosage of the individual preparations nolonger exists.

In a further preferred embodiment the combination preparation containsas a further component a preparation which has a suppressive activity onTNF-alpha. Preferably, this is a gluco-corticosteroid, such as e.g.cortisone, a cortisol analogue or prednisolone derivative or anantimetabolite of folic acid, such as e.g. methotrexate. Preferredcompounds are prednisone, prednilolone, 6 α-methyl-prednisolone,triamcinolone, paramethasone, dexamethasone, betmethasone, cortisone,cortisol and 16-methylene-prednisolone. The antiinflammatory activity ofthe EPO/iron dose is intensified synergistically.

When using the combination preparations, it is possible to administerthe preparations, preferably the EPO preparation and the ironpreparation, in a so-called fixed combination, i.e. in a singlepharmaceutical formulation in which the compounds are present. This cancomprise e.g. injection solutions, infusion solutions or lyophilizates,which, for example, are filled into ampoules. This administration formhas the advantage that the EPO preparation is stabilized by the ironcomplex during the production and the storage of the administrationform. The fixed combination of the active substances in the form of alyophilizate has the further advantage of simple and safe handling. Thelyophilizate is dissolved in the ampoule by the addition ofpharmaceutically usual injection media and administered intravenously.

It is also possible to provide the preparations in the form of separatepharmaceutical formulations. As a rule, this is effected in the form ofan individual unit pack which comprises several containers, with thefirst container being an administration form (lyophilizate, injectionsolution or infusion solution) containing the erythropoietin preparationand the second container being a suitable administration form for theiron preparation and optionally the third container being a suitableadministration form of a TNF-alpha suppressor. The unit packs can alsocontain several individual dosage preparations of the respectivepreparations, so that, for example, a unit pack contains the requisitenumber of individual administration forms for a particular period (e.g.for weekly dosing).

This free combination, which can be made available in a single unit pack(medicament pack) also has the advantage that each patient to be treatedcan be prescribed a particular individual amount of an EPO preparation,of an iron preparation and optionally of a TNF-alpha suppressor.Furthermore, these combination preparations offer the advantage ofgreater safety when performing the therapy, since in each case theoptimal synchronized amount of the individual preparation is fixed and amistake with otherwise commercially available individual preparations,which are supplied in different dosages, can be largely excluded.Moreover, it has to be borne in mind that that in different countriesmedicinal preparations are often commercialized in different dosages forreasons of national requirements and there accordingly exists anincreased danger of mistake with varying proportional amounts of theindividual active substances. Further, the combination preparations inaccordance with the invention minimize the risk of an inadvertently toohigh iron dose, which can possibly be given when conventional ironpreparations from separate medicament packs are used together with thedose of an erythropoietin preparation. A safe therapy and simplehandling by the personnel performing the treatment or in the area ofself medication performed by patients is guaranteed by the combinationpreparation in accordance with the invention. In the present case it ise.g. also possible to provide one active substance as an injectionsolution and the other active substance (iron complex) as anadministration form for oral administration.

Where the EPO preparation is made available as a lyophilizate, themedicament packs (combination packs) contain the corresponding amount ofthe EPO preparation in glass ampoules or in cartridges. The ironpreparation can be present in solid form (tablet, powder, granulate,lyophilizate, etc) or also in liquid form in a separate container.Further, the combination pack preferably contains a reconstitutionsolution in order to dissolve either the active substance lyophilizatealone or also together with the solid iron preparation. If the ironpreparation is present as a ready-for-use solution, the solution can bemixed together with the EPO solution when the combined administration ofEPO and iron preparation has to be effected. Basically, the ironpreparation can also be made available as a concentrate for addition toconventional infusion solutions, by which means a longer administrationover several hours can be effected. In this case, a smaller volume ofthe iron complex-containing solution (about 0.5-10 ml) is added to theready-for-use injection solution of about 500-1000 ml.

Combination preparations in the meaning of the present invention arealso those unit packs which have a fixed optimal amount of the EPOpreparation and of the iron preparation to be administered weekly.Advantageously, 5,000-50,000 U of an EPO preparation are administeredweekly. This total dosage can be divided into several partial dosagesfor daily administration (i.e. 7 times per week) or for theadministration of 1-6 partial amounts per week. The amount of the ironpreparation to be administered weekly can be optionally divided into anamount corresponding to the weekly total dosage or also into severalpartial amounts for a repeated administration per week together with theerythropoietin preparation.

A further possibility in the meaning of the present invention comprisesproviding in each case individual administration forms of theerythropoietin preparation or of the iron preparation as an independentmedicament, with the individual preparations being formulated such thatthey contain the requisite amounts of the individual substances for thecombination in accordance with the invention of the EPO preparation andof the iron preparation. As a rule, the medicament packs contain thepreviously described package insert containing correspondinginstructions for the combined administration with EPO or with ironpreparations in the required amounts. A corresponding instruction canalso be present as a pack imprint on the medicament pack (secondarypackaging) or on the primary packaging (ampoule, blister strips, etc.).Thus, in the case of the EPO-containing medicament with 250-20,000 U ofEPO it is, for example, indicated thereon that this preparation shouldespecially be administered together with an iron complex preparationcontaining 1-40 mg, preferably 5-30 mg, of iron. In the case of the ironpreparation there is a reverse indication to the combined administrationwith 250-20,000 U of an erythropoietin preparation.

A further possibility for providing the EPO preparations comprisesmaking available corresponding multi-dose preparations which contain theEPO preparation in higher amounts compared with individual doses. Thesepreparations are especially suitable for use in clinics in which a largenumber of patients are treated daily. These multi-dose preparationscontain the EPO preparations in dosages of up to 500,000 U, especiallyup to 100,000 or 50,000 U. The multi-dose preparations have theadvantage that they permit the skilled medical personnel to withdraw anydosage of the EPO preparation, for example by withdrawing correspondingamounts by volume of the finished injection solution. This is especiallyadvantageous in the treatment of patients with different dosagerequirements of the active substance or in the treatment of children inwhich a lower dosage of the EPO preparation is required. From aninjection solution of, for example, 100,000 U of an EPO preparation,preferably freshly prepared at the beginning of the day, there can beperformed, circumstances permitting, all patient treatments requiredduring this day without the need to prepare separate injection solutionsfor each of the individual patients. This can lead to a significant timesaving or to an easing of the burden of work for skilled medicalpersonnel. Preferably, the individual EPO dosages are withdrawn in therange of 250 U, 500 U, 1,000 U and 10,000 U.

The multi-dose preparations can also be present in the form ofsolutions, which are filled into cartridges. These cartridges aresuitable for use in so-called pens, which permit administration bypatients themselves and an individual dosage withdrawal. For example,these cartridges contain the EPO preparation in an amount of 10,000 or20,000 U, whereby dosing intervals of, for example, 250 U, 500 U, 1,000U or 2,000 U are possible by appropriate adjustment of the withdrawalvolume.

The production of the pharmaceutical administration forms is effectedaccording to usual processes known in galenical technology usingpharmaceutically usual adjuvants.

In connection with the diagnosis of rheumatic diseases and of ironmetabolism disorders, especially the serum ferritin concentration can bedetermined in the meaning of the present invention. When a true irondeficiency occurs in addition to an already present rheumatic disease oranaemia, then the ferritin does not increase (it mainly remains below90-95 ng/ml). In the case of simultaneous clinical symptoms ofinfection, inflammation or malignant disease this value points to acombination of iron deficiency and anaemia in conjunction with arheumatic disease. Since the serum ferritin in these diseases can alsoreact in the sense of an acute phase protein, the erythrocyte ferritincan be evaluated better diagnostically. The iron which is not requiredfor erythropoiesis is stored by means of transferrin in two types ofstorage pools. The most important store is ferritin. This is aheterogeneous family of proteins which surrounds an iron nucleus. It issoluble and represents the active storage form in the liver(hepatocytes), bone marrow, spleen (macrophages), erythrocytes and inthe serum (about 100-300 μg/l). The tissue ferritin pool is very labileand rapidly available when iron is required. The circulating serumferritin originates from the reticuloendithelial system and itscirculating concentration runs parallel with the total body iron (eachng/ml corresponds to 8 mg of iron reserve).

In performing the combination therapy with the combination preparationin accordance with the invention the weekly maximal dosage can bedecided in a very simple manner by determining the diagnostic parametersfor the iron status, especially the iron, transferrin, transferrinsaturation, transferrin receptor and ferritin parameters. The patient isindicated to be optimally adjusted in the correction and maintenancephase when

ferritin is: 100-300 μg/l (corresponding to stored iron(III) of 800-1200mg) and the

transferrin saturation is: 20-40%.

Preferably, the ferritin concentration is at least 100 μg/l, especiallyat least 150 μg/l, and a maximal up to 300 μg/l, especially a maximal upto 250 μg/l. The iron concentration is advantageously between 10-20μmol/l (corresponding to about 56-112 μg/dl) and the transferrinconcentration is between 30-60 μmol/l (corresponding to about 240-480mg/dl). The transferrin saturation is defined as the ratio ofserum/plasma iron concentration to serum/plasma transferrinconcentration (multiplied by a correction factor of 1.41). It is thus anon-dimentional number which is independent of the hydration status ofthe patient. The transferrin saturation is calculated according to theformula

Transferrin saturation (%)=(iron [mg/dl]×100)/(transferrin [mg/dl]×1.41)

An optimal adjustment of the patient is achieved when the ratio oftransferrin saturation (in %) to the ferritin concentration (in μg/l)lies in the range of 5-40%. This parameter is defined as thetransferrin/ferritin saturation (TfF saturation). It is calculatedaccording to the formula

TfF saturation=(transferrin saturation in %)×100/(ferritin [μg/l])

The value for this parameter preferably lies in the range of 10-40,especially at 15-25 [%×1/μg].

The optimal adjustment of the patient is checked diagnostically by meansof this parameter, e.g. with the administration of 1 to 6 ampoules,preferably up to 3, 4 or 5 ampoules, in the week (one ampoule contains500-7,500 U of rhEPO and 1-20 mg of iron complex).

In order to reliably exclude undesired side effects, the acute phaseparameter CRP (5 mg/l±100%)[CRP=C-reactive protein] is measured, withthe CRP at present being the best protein marker of an inflammatoryreaction. Other parameters are TNF-alpha (Tumor Necrosis Factor alpha)and IL-6 (interleukin 6) or IL-1, IL-2 and IL-8. TNF-alpha should be <30pg/ml (in plasma, ELISA) and IL-6 should be <20 pg/ml (in plasma,ELISA). In addition, the liver parameters GPT (glutamate pyruvatetransaminase), GOT (glutamate oxalacetate transaminase) and γ-GT(gamma-glutamyl transferase) can be determined and should lie in thefollowing ranges (determination at 37° C.): GPT:<50 U/l; GOT:<50U/l;γ-GT:<40 U/l . In this connection, the GPT parameter currentlystands in first position in liver diagnostics.

Furthermore, if desired, the haematological control parameters such ashaematocrit (amount of red blood corpuscles in the total volume) or theincrease in hypochromic erythrocytes can be relied upon. When thecontrol parameters show a high increase, the weekly iron dose has to bereduced and then additional rhEPO should be administered. When thecontrol parameters, primarily the transferrin saturation, show a lowervalue, the weekly iron dose has to be increased.

Furthermore, in the meaning of the present invention it has surprisinglybeen found that the establishment for patients of an individual optimaltherapeutic dosage of EPO and of iron ions for the treatment of anaemiacan be effected by determining the soluble TfR (transferrin receptor).The optimal therapeutic dosage of EPO and of iron(III) is obtained whenthe concentration of soluble TfR no longer increases. In order to insurethat sufficient mobilizable iron is present, the i.v. iron dose and theEPO dose are increased in turn until a plateau has been reached. Thiscorresponds to a concentration of 1,500-2,000 μg/l TfR.

In performing the combination therapy with the combination preparationin accordance with the invention for treatment of anaemia the weeklymaximal dosage can be decided in a very simple manner by determining thediagnostic parameters transferrin receptor (TfR) and ferritin and theratio of TfR to ferritin. The patient is indicated to be optimallyadjusted in the correction and maintenance phase when

ferritin is: 100-300 μg/l (corresponding to stored iron(III) of 400-1200mg) and

TfR/ferritin is: >15.

The TfR concentration is advantageously between 1,500-2,500 μg/l. Theratio of the concentrations TfR (in μg/l) to ferritin (in μg/l) liesespecially in the range of 15-35, preferably at values above 20.

The optimal adjustment of the patient is checked diagnostically by meansof this parameter, e.g. with the administration of 1 to 6 ampoules,preferably up to 3, 4 or 5 ampoules, in the week (one ampoule contains,for example, 3,000 U of rhEPO and 5 mg of iron complex. In thisconnection, these are not haemodialysis patients, but patients (e.g.rheuma patients) who, because of otherwise caused anaemia, are treatedwith EPO and/or iron preparations.

As already indicated, in order to reliably exclude undesired sideeffects, the acute phase parameter CRP (2-10 mg/l)[CRP=C-reactiveprotein] is measured; in addition the liver parameter GPT (glutamatepyruvate transaminase), which should be <50 U/l at 37° C. (<30 U/l at25° C.) can be determined. Furthermore, if desired, the haematologicalcontrol parameters such as haematocrit (amount of red blood corpusclesin the total volume) or the increase in hypochromic erythrocytes can berelied upon. In this connection, the reticulocytes can increase to avalue of up to 15/1,000-30/1,000. The typical haemoglobin concentrationlies at 12-18 g/dl. When the soluble TfR shows a high increase, theweekly iron dose has to be increased to up to 35 mg. When the solubleTfR shows lower values, the weekly EPO dose has to be increased.

The determination of the iron status is effected by the analysis ofsamples of body fluids (blood, serum, urine, etc.) of the patients inquestion. In order to determine the iron status, the concentration ofiron, transferrin, ferritin and transferrin receptor, the transferrinsaturation and the transferrin/ferritin saturation are determined inparticular. In the case of haemodialysis patients, the parameters iron,transferrin, ferritin and transferrin saturation are preferablydetermined according to usual analytical methods. The determination ofthe transferrin/ferritin saturation value is especially relevant. In thecase of anaemia patients whose anaemia is not caused by haemodialysis,the ferritin concentration and the concentration of the transferrinreceptor are primarily determined. The determination of the ratio oftransferrin receptor to ferritin (transferrin receptor/ferritinsaturation value) is especially relevant.

In this sense, an optimal combination preparation in accordance with theinvention for the treatment of patients with rheumatic diseasescomprises 500-10,000 U, especially 2,000-4,000 U, of an EPO preparationand 3-10 mg, preferably 5 mg, of iron ions, preferably a Fe(III)complex, whereby the EPO preparation and the Fe(III) complex can bepresent in separate administration forms or in a single administrationform. The administration forms in accordance with the invention alsopermit an administration of the iron preparation 1 to 3 days prior tothe EPO preparation in order to top up the iron store prior to thebeginning of the EPO treatment

The concentration of iron in the blood and the iron binding capacity aredetermined in clinical chemistry in order to investigate ironmetabolism. Both tests should always be carried out, since the relationof their measured results to each another is important Usually, thenormal serum levels lie between 75 and 150 μg/dl in men and between 60and 140 μg/dl in women. The total iron binding capacity is between 250and 450 μg/dl. The serum iron level varies over the course of the day.It is lowered in the case of iron deficiency and in the case of anaemiasassociated with chronic illnesses. It is increased in the case ofhaemolysis and in the case of syndromes with iron over-loading (e.g.haemochromatosis or haemosiderosis). Patients under oral iron medicationcan have normal iron serum levels, although actually an iron deficiencyis present in them. The total iron binding capacity (=transferrin×2) isincreased in the case of iron deficiency; on the other hand it islowered in the case of anaemias in the course of chronic illnesses.

Moreover, the serum ferritin level is determined. Ferritin is aniron-storing glycoprotein, of which tissue-typical isoferritins existand which can be determined immunologically in serum, e.g. by aradioimmunoassay (RIA) or also by turbidimetric methods. The ferritinvalue is a measurement of the iron store in tissue. In most laboratoriesthe normal range lies between 30 and 300 ng/ml and the geometric medianvalue is 88 in men and 49 in women. The serum ferritin values stand inclose relation to the total iron store of the body. Therefore, a loweredserum ferritin level is found only in the case of iron deficiency. Anincreased level is found in the case of iron over-loading. Likewise, anincreased serum ferritin level is found in liver damage or inassociation with many neoplasms where ferritins can also be bonded toacute phase proteins. The serum transferrin receptor can also bedetermined by an enzyme-enhanced immunoabsorption test (enzyme-linkedimmunosorbent assay=ELISA). In this, a monoclonal antibody against thesoluble receptor is used. The reference range lies between 0.5-3 mg/l.The level is increased in the case of a slight deficiency in the ironstores. The concentrations of specific erythrocyte ferritins can bedetermined in order to characterize the iron store, especially when theserum ferritin is not utilizable in the case of tissue damage or byacute phase reactions.

Further, the erythrocyte ferritin level is also determined in order toinvestigate the iron metabolism. The erythrocytes are separated from theleukocytes and thrombocytes (which likewise contain ferritin) inheparinized blood by centrifugation. Lysis of the erythrocytes and theimmunological determination of the stored ferritin then follow. Theerythrocyte ferritin reflects the status of the iron store during thepreceding 3 months (i.e. during the lifetime of an erythrocyte). Thenormal values generally lie between 5 and 48 atom gram (ag) pererythrocyte. Values<5 are found in iron deficiency anaemias and elevatedvalues (often >100) are found in the case of iron over-loading (e.g.haemochromatosis). The determination of zinc protoporphyrin has asimilar affirmative validity.

The invention is illustrated hereinafter on the basis of an examplewhich has been performed.

EXAMPLE 1

11 patients with visible rheumatoid arthritis and chronic inflammatoryanaemia (Hb in the case of women <12 g/dl, in the case of men <13 g/dl)were treated over 12 weeks with 150 IU of EPO/kg body weight 2× weeklys.c. and additionally by i.v. administration of iron sucrose 200 mg/weekon the appearance of a functional iron deficiency. A subsequentobservation period took place over a further 12 weeks.

The course of therapy was investigated on the basis of the primaryefficacy criteria (vitality scale SF-36, fatigue scale (MAF), isometricmuscle strength (MSI)) and the secondary efficacy criteria, namely thedisease activity parameters DAS (Disease Activity Score), RADAI(Rheumatoid Arthritis Disease Activity Index) as well as acute phaseparameter CRP (C-reactive protein):

RESULTS

As will be evident from attached FIG. 1, the therapy proceededpositively. With respect to muscle strength, an average MSI increase of8% was recorded, the vitality rose on average by 14% on the vitalityscale SF-36 and the fatigue could be lowered by 8.3 out of 50 possiblepoints.

The effects of the therapy on the disease activity parameters DAS, RADAIand CRP can be concluded from FIG. 2.

Thus, at the commencement of therapy the DAS had a value of 6.5, whichlay at 5.67 at the end of therapy. The RADAI was 5.29 at thecommencement of therapy and 4.57 at the end of therapy, and CRP (mg/dl)was 3.47 at the commencement of therapy and 2.99 at the end of therapy.

What is claimed is:
 1. A method of treating the activity of a rheumaticdisease in patients comprising administering to said patient sufferingfrom said rheumatic disease a combination therapy comprising a firstcomponent consisting of 250 to 15,000 U of an erythropoietin preparationand a second component, consisting of an amount of a physiologicallycompatible iron preparation, which iron preparation administers to saidpatient from 1 to 40 mg of iron ions, each said components in saidcombined therapy being administered from 1 to 7 times weekly with thetotal amount of iron ions administered to said patient being no greaterthan 100 mg per week and administering said combination therapy for aperiod of time sufficient to reduce the activity of said disease.
 2. Themethod of claim 1, wherein each erythropoietin administration containsfrom 500 to 10,000 U of erythropoietin.
 3. The method of claim 1,wherein each iron preparation administration corresponds to anequivalent amount of from 1 to 30 mg of iron ions.
 4. The method ofclaim 3, wherein each iron preparation administration corresponds to anequivalent amount of from 3 to 20 mg of iron ions.
 5. The method ofclaim 1, wherein each erythropoietin administration contains from 250 to20,000 U of erythropoietin and each iron preparation administrationcorresponds to an equivalent amount of from 1 to 30 mg of iron ions. 6.The method of claim 5, wherein each erythropoietin administrationcontains from 500 to 10,000 U of erythropoietin and each ironpreparation administration corresponds to an equivalent amount of from 3to 20 mg of iron ions.
 7. The method of claim 1, wherein the ironpreparation is a complex having a molecular weight from 30 kilodaltonsto 100 kilodaltons.
 8. The method of claim 7, wherein the ironpreparation is Fe(III) saccharate.
 9. The method of claim 7, wherein theiron preparation is Fe(III) gluconate.
 10. The method of claim 1, wheresaid iron preparation is administered to said patient in an amount toprovide no more than 50 mg of iron ions per week.
 11. The method ofclaim 1, wherein the rheumatic disease is an inflammatory joint disease.